BUFFALO, N.Y. -- For more than a decade, researchers have tried
to figure out the role of a membrane transport protein involved
with a rare, hereditary condition that results in vision loss.
Numerous papers have been published, but no single strong
hypothesis has emerged.

Now, a team of University at Buffalo researchers led by Mark
Parker, PhD, assistant professor in the Department of Physiology
and Biophysics in the Jacobs School of Medicine and Biomedical
Sciences, has proposed a single, unifying model for the SLC4A11
protein. The research is relevant to the rare disorder Congenital
Hereditary Endothelial Dystrophy (CHED), in which SLC4A11 mutation
results in vision loss by affecting cells in the cornea as well as
hearing loss.

The UB researchers describe SLC4A11 as a highly-selective
acid-conducting protein that regulates the pH level of cells.

The research was published online Sept. 28 in the American
Journal of Physiology--Cell Physiology. Evan J. Myers, a doctoral
candidate in the UB Department of Physiology and Biophysics, is
first author.

The paper is accompanied by an editorial by Keith Nehrke of the
University of Rochester School of Medicine and Dentistry, who cited
the UB researchers’ “robust data and detailed
analysis,” noting that the work on the protein
“suggests that it utilizes a novel conductance pathway to
support corneal physiology and health.”

SLC4A11 is a clinically important protein found in endothelial
cells in the cornea, the inner ear and the kidneys. The protein is
in the SLC4 family of transport proteins that are of interest in
part because they’re linked to disorders ranging from
blindness and epilepsy to hypertension and cancer; they also are
implicated in a rare disease in which an individual’s blood
becomes acidified.

Varying hypotheses

Parker began working on SLC4A11 in 2001 when he was involved in
the original cloning of the gene as a postdoctoral scholar at the
University of Bristol in England.

“The function of the protein eluded us at the time so I
moved onto working with other related proteins,” he said.

In the intervening decade numerous papers were published
hypothesizing that SLC4A11’s function was to transport
various molecules, including boron, sodium, ammonium and water.

But few of those data have been repeated, and much of the data
was controversial, Parker said. So having established a new
laboratory at UB, Parker and Myers began to look at the protein
again in 2014.

“In order to develop a therapy to restore vision and
hearing in individuals with SLC4A11 mutations, we need to
understand how SLC4A11 normally promotes eye and ear health,”
said Parker. “Perhaps the most crucial question is,
‘what does this protein transport?’ ”

“Our research found that the Slc4A11 protein transports
the equivalent of pure acid, only the second such protein
identified in mammals,” said Parker.

His focus on the SLC4 family of membrane proteins has been
concerned with how cells attempt to maintain the proper pH level,
essential for healthy functioning.

“Blood plasma needs to stay at a pH of 7.4, and most cells
maintain an internal pH close to 7.2,” said Parker
“Those are the magic numbers.” Even slight deviations
can result in devastating physiological effects, he added.

Healthy corneal cells

“Corneal cells are no exception. It’s very important
to maintain that pH balance in the cornea,” Parker explained.
“That means the tissues stay properly hydrated and
transparent, which allows light to pass to the lens without
distortion.”

The role of SLC4A11 had always been a mystery, he explained,
because there seemed to be other acid- and alkali-transporter
proteins in corneal cells that also are capable of balancing
pH.

“We find SLC4A11 to be a very flexible protein that can
either move acid into or out of a cell depending on prevailing
conditions,” he said.

If the actions of the acid- and alkali-transporting proteins in
the cornea are not perfectly balanced, he continued, then the pH
will be disturbed and these cells will not function
effectively.

“We propose that SLC4A11 acts as sort of an overseeing
manager, able to rapidly redress any pH imbalance, ensuring that
the cells function properly,” said Parker.

The research was supported by startup funds from UB, by a Carl
W. Gottschalk Research Scholar Grant from the American Society of
Nephrology, and by the National Institutes of Health.

In addition to Parker and Myers, co-authors are Aniko Marshall,
a research technician with the UB Department of Physiology and
Biophysics and Michael L. Jennings with the University of Arkansas
for Medical Sciences. Parker also has appointments with the UB
Department of Ophthalmology and the State University of New York
Eye Institutes.

Earlier this year, Parker and his colleagues at UB and other
institutions published a paper in the Journal of Physiology on
another protein in the same family. That study, performed in
collaboration with a team of physicians in Beijing, described a
novel case of a rare disease called proximal renal tubular acidosis
(pRTA). This disease is caused by mutations in SLC4A4 (a close
relative of SLC4A11), a membrane transport protein that neutralizes
blood acid by supplying the plasma with sodium bicarbonate (baking
soda). Individuals with pRTA have acidic blood and numerous eye
defects such as cataracts and glaucoma.

Parker’s lab showed that the SLC4A4 protein in that case
was not able to do its job due to being misfolded, which in turn,
causes it to be withheld from the cell membrane. An image of a
kidney cell expressing the displaced mutant protein was shown on
the journal cover.